The persistent maladaptive behavioral changes that are associated with drug addiction reflect plasticity at the level of neurons and synapses. In general, stable forms of plasticity require protein synthesis, and even weak events can produce long-lasting changes under conditions where protein synthesis is active. We hypothesize that drug-induced plasticity, both behavioral and synaptic, can be disrupted by the formation of stable competing associations, and this disruption is enhanced when protein synthesis is facilitated. Specifically, we predict that inhibitors of glycogen synthetase kinase 3 (GSK3), which facilitate protein synthesis by increasing the synthetic capacity of neurons, will promote the reversal of cocaine-induced plasticity and reduce drug-seeking behavior. Specific aims. Behavioral and electrophysiological studies will be used to address two specific aims: - Do GSK3 inhibitors reduce the likelihood that rats who were previously taught to self-administer cocaine will return to drug-seeking behavior after extinction? - Can GSK3 inhibitors help to reverse the synaptic plasticity that is induced in the ventral tegmental area (VTA) by cocaine exposure? Long-term objectives. If positive results are obtained, these studies will open the way to developing GSK3 inhibitors as a treatment for drug addiction, where they would enhance effectiveness of cognitive therapy in disrupting drug-seeking behavior. Relevance to NIDA's mission. Drug craving and relapse have been the most difficult problems to solve in treating drug abuse, and innovative approaches are required to improve the outcome for the millions of Americans who are addicted to cocaine and other drugs. Importance to basic research on addiction and synaptic plasticity. Overwhelming evidence points to the VTA as a key brain region in drug addiction, but the mechanism of drug addiction at the synaptic level remains poorly understood, and even less is known about the reversibility of drug-induced plasticity. This proposal will shed light on those areas, and on the role of GSK3 in controlling the stability of newly-formed associations. Summary of experimental design and methods. Rats trained to self-administer cocaine (drug delivery upon active lever pressing, associated with presentation of cue light) will be studied with regard to plasticity in the VTA, using slices prepared from their brains. In other rats, we will extinguish the lever-pressing behavior in the presence or absence of a GSK3 inhibitor, and later we will either test how likely the animals are to return to lever-pressing (drug-seeking behavior), or we will sacrifice the animals to determine if cocaine-induced plasticity in the VTA was reversed. PUBLIC HEALTH RELEVANCE: Cocaine and other addictive drugs produce very persistent and detrimental changes to regions of the brain that evaluate the reward value of stimuli and experiences. Improvements in our understanding of these modifications at the behavioral and physiological levels, and the identification of possible methods for their disruption, will lead to new therapies to reduce the likelihood of relapse in drug abusers. In this project, we will explore the possibility of reversing cocaine-induced effects on behavior in rats trained to self-administer cocaine, and on synaptic function in a brain area that evaluates the reward value of stimuli and experiences.